Download Cancer Prone Disease Section X-linked lymphoproliferative disease (XLP) in Oncology and Haematology

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Cancer Prone Disease Section
Review
X-linked lymphoproliferative disease (XLP)
Hamid Bassiri, Kim E Nichols
Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA (HB),
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, United States (KEN)
Published in Atlas Database: April 2012
Online updated version : http://AtlasGeneticsOncology.org/Kprones/XlinkedlymphoproliferID10028.html
DOI: 10.4267/2042/47545
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
reduced or absent expression of the encoded proteins.
De novo mutations in either gene are rare. Female
SH2D1A or XIAP mutation carriers are clinically
unaffected yet at risk to transmit the mutant allele to
50% of male offspring, who will have XLP. Female
offspring of XLP carriers are at 50% risk to inherit a
mutant allele and thus be carriers of XLP.
Identity
Note
Two subtypes of XLP have been idenitified to date.
XLP type 1, (also known as Duncan disease, Purtilo
syndrome) is a rare primary immunodeficiency, first
described by Purtilo (Purtilo et al., 1974), in which
patients develop dysgammaglobulinemia (most
commonly hypogammaglobulinemia of one or more
immunoglobulin subclasses), fulminant mononucleosis
following infection with Epstein Barr virus (EBV), and
B-cell lymphoma.
XLP1 is caused by mutations in SH2D1A (formerly
DSHP; SAP), which encodes the cytoplasmic adaptor
protein Signaling Lymphocytic Activation Molecule
(SLAM)-associated protein (SAP) (Coffey et al., 1998;
Sayos et al., 1998).
XLP type 2, (Rigaud et al., 2006) is a clinically similar
disorder that predisposes primarily to hemophagocytic
lymphohistiocytosis (HLH), which often presents in the
setting of primary EBV infection.
Patients with XLP2 may also exhibit splenomegaly,
hypogammaglobulinemia and hemorrhagic colitis
(Marsh et al., 2010). To date, no patient with XLP2 has
been
reported
to
develop
abnormal
Blymphoproliferation or lymphoma. XLP2 is caused by
mutations in XIAP (BIRC4), the gene encoding the Xlinked inhibitor of apoptosis protein.
Inheritance
XLP1 and -2 are transmitted in an X-linked fashion and
do not have a known ethnic or racial predilection. The
causative genes are located in proximity to one another
at Xq25.
Mutations in SH2D1A or XIAP are identified in 8397% of XLP1 and 12% of XLP2 patients, respectively
(Filipovich et al., 2011).
Mutations include insertions, deletions of one or more
exons and nucleotide substitutions that result in
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(9)
Clinics
Note
XLP is estimated to affect 1-3 per million male
individuals, although the incidence may be higher as
the condition may go undetected. Nonetheless, any
male individual presenting with severe or fatal EBV
infection, or HLH as a result of EBV exposure should
be evaluated for XLP, especially if there is a family
history
of
maternally
related
males
with
dysgammaglobulinemia, lymphoma or EBV-induced
HLH. Early diagnosis of XLP is paramount, as the
mean ages of death of individuals with XLP1 and
XLP2 are 11 and 16 years, respectively (Pachlopnik
Schmid et al., 2011).
Phenotype and clinics
XLP1 patients usually present with fulminant FIM (a
hyperinflammatory condition resembling HLH that is
induced by EBV infection and typified by the
dysregulated expansion of EBV-infected B cells and
cytotoxic T cells, and the abnormal activation
of macrophages), dysgammaglobulinemia and B cell
lymphoma. Less commonly, XLP1 manifests as
lymphocytic vasculitis (usually involving the lungs or
central nervous sytem [CNS]), aplastic anemia or
lymphatoid granulomatosis (Gaspar et al., 2002). The
manifestations of XLP1 can occur in the absence of
EBV infection.
XLP2 commonly presents with splenomegaly and
recurrent episodes of HLH, often in response to EBV
685
X-linked lymphoproliferative disease (XLP)
Bassiri H, Nichols KE
(Milone et al., 2005), and should be considered in any
XLP1 or -2 patient who experiences primary EBV
infection.
Lymphomas can be effectively treated with standard
chemotherpateutic regimens; however, patients should
be carefully monitored for the development of EBV
and other infections, which can be difficult to manage
due to underlying immune defects.
Patients with hypogammaglobulinemia are treated with
monthly immunoglobulin replacement.
Asymptomatic patients with XLP should be
periodically monitored for immunoglobulin levels,
evidence for EBV exposure, and signs of development
of other manifestations of disease.
infection.
XLP2
patients
also
display
dysgammaglobulinemias, and a proportion of affected
individuals develop hepatitis and/or colitis.
There is no known correlation between SH2D1A or
XIAP genotype and phenotype in XLP1 or XLP2.
Affected members of the same family may exhibit
significant variability in presentation.
Diagnosis is generally suspected based on clinical
history. Screening tests can be performed to assess for
protein levels of SAP or XIAP in lymphocytes via flow
cytometry, and the diagnosis confirmed by genetic
analysis of the associated genes. In rare instances,
genetic analysis fails to identify an abnormality in
SH2D1A or XIAP in a host presenting with signs and
symptoms consistent with XLP.
Genes involved and proteins
Neoplastic risk
SH2D1A
The risk for development of lymphomas in XLP1
approaches 25-30%, with a mortality rate of 9% (Booth
et al., 2011). The lymphomas are typically high grade
non-Hodgkins type B cell lymphomas. Lymphomas
tend to be extranodal and involve the intestines,
although they can also be found in liver, kidneys and
CNS. Histologically, they are classified as Burkitt's,
immunoblastic, small cleaved B cell lymphomas or
mixed cell lymphomas. Not all lymphomas carry
evidence of EBV genome. It remains poorly understood
why patients with XLP1 develop lymphoma; however,
absence of invariant natural killer T (NKT) cells and
defects in T and NK cell cytotoxic function may
contribute to lymphoma formation.
Note
XLP1. SH2D1A consists of 4 exons spanning 25 kb of
genomic DNA and encodes a 128 amino acid protein
comprised primarily of a Src Homology 2 (SH2)
domain. Over 70 disease-associated mutations have
been identified (Filipovich et al., 2011).
Protein
Note
SH2D1A encodes the SLAM (Signaling Lymphocytic
Activation Molecule)-associated protein (SAP), which
is required for signaling through the SLAM family of
receptors (SLAM, 2B4, CD84, Ly108/NTB-A, Ly9).
Loss of SAP expression and/or function results in
immune cell defects, including reduced T and NK cell
cytotoxicity, impaired follicular T helper cell function
resulting in poor germinal center formation, decreased
restimulation-induced T cell death, altered Th2-type
cytokine production and abrogation in NKT cell
development (Rezaei et al., 2010; and references
therein).
Treatment
The therapy of choice for XLP patients is
hematopoietic cell transplantation (HCT). HCT is the
only known curative treatment and has the best chance
of success if performed as early as possible - before the
onset of other disease manifestations. Other therapies
directed at treating the manifestations of XLP may be
necessary before HCT is attempted. Although HCT
carries its own risk of complications and mortality,
without it only 50% of XLP1 patients reach adulthood.
The majority perish secondary to HLH (70%),
lymphoma (12%) or myelodysplasia (6%) (Booth et al.,
2011; Pachlopnik Schmid et al., 2011). The prognosis
is similarly poor for XLP2 without HCT, in which
mortality is attributed to HLH (30%), colitis (23%),
liver failure (8%), and infectious causes (8%)
(Pachlopnik Schmid et al., 2011).
HLH is generally treated with corticosteroids,
cyclosporine, and etoposide. Rituximab has been used
successfully to prevent EBV-induced FIM in XLP1
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(9)
XIAP
Note
XLP2. XIAP consists of 6 exons spanning 42 kb and
encodes a 497 amino acid protein. The XIAP protein
contains 3 Baculovirus IAP Repeat domains and a Cterminal Ring domain with E3 ubiquitin ligase activity.
XIAP binds the tumor necrosis factor receptorassociated factors TRAF1 and TRAF2 and inhibits
apoptosis through interactions with caspases 3,
caspases 7, and caspases 9. It is still unclear how
mutations in XIAP and the resulting disinhibition of
apoptosis result in the manifestations of XLP2.
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X-linked lymphoproliferative disease (XLP)
Bassiri H, Nichols KE
Schematic representing the putative mechanism of SAP-mediated signaling. (A) In the absence of SAP, signaling from the SLAM
family receptors is impaired due to the binding of inhibitory phosphatases, such as SHP-1, SHP-2 or SHIP. Via a unique portion of its
SH2 domain, SAP binds to the Src family tyrosine kinase Fyn, which leads to the activation of Fyn's kinase activity. (B) Engagement of
SLAM family receptors via homotypic or heterotypic interactions with similar receptors on neighboring cells leads to a conformational
change in the SLAM receptor tails, thereby facilitating the binding and SAP and Fyn. (C) Fyn then phosphorylates specific tyrosines
within the SLAM receptors, which form docking sites for additional signaling proteins, and allow the transmission of signals required for
cell functions, such as Th2 type cytokine production, cytotoxicity and natural killer T cell development.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(9)
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X-linked lymphoproliferative disease (XLP)
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This article should be referenced as such:
Rigaud S, Fondanèche MC, Lambert N, Pasquier B, Mateo V,
Soulas P, Galicier L, Le Deist F, Rieux-Laucat F, Revy P,
Fischer A, de Saint Basile G, Latour S. XIAP deficiency in
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(9)
Bassiri H, Nichols KE. X-linked lymphoproliferative disease
(XLP). Atlas Genet Cytogenet Oncol Haematol. 2012;
16(9):685-688.
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